The accumulation of amyloid beta-peptide (ABeta) is an early and necessary step in the pathogenesis of Alzheimer's Disease (AD). ABeta is generated from the amyloid beta-protein precursor (APP) by two sequential proteolytic cleavages mediated by beta- and gamma-secretases (20). If the action of these secretases could be impaired, ABeta deposition might decline and, in turn, the pathogenesis of AD could be halted. Our preliminary data suggests that sortilin, a 100kDa neurotensin receptor and putative trafficking molecule, is downregulated in AD patient-derived postmortem brain tissue. Furthermore, suppression of endogenous sortilin in cultured cells, using RNA interference, increases ABeta generation suggesting that sortilin may be a modulatory factor in ABeta biogenesis. In light of our findings, the specific aims of this project include: evaluating the role of sortilin in APP processing and ABeta deposition, determining the relevant protein interactions of sortilin and their subcellular localization, and determining the expression pattern of sortilin in human brain tissue. This is to be accomplished through a variety of techniques, some including: immunofluorescence, subcellular fractionation, RNAi, Western blot, and ELISA. [unreadable] [unreadable]